• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel compounds of the formula: wherein R is an aromatic or heterocyclic group, which may optionally be substituted, R2 is a methyl group, a hydroxymethyl group, a nitroxymethyl group, a formyl group, a nitrogen-containing five-membered ring-menthyl group, an acetal-methyl group, a trialkylsilyloxymethyl group, an alkyl-or aryl-sulfonyloxymethyl group, an alkyl- or aryl- sulfonylaminocarbonyloxymethyl group, an acyloxymethyl group, an alkoxycarbonyloxymethyl group, a halogenomethyl group, an alkoxymethyl group, an aryloxymethyl group, a cyano group, a carbamoyl group which may optionally be substituted, a carbamoyloxymethyl group which may optionally be substituted, a thiocarbamoyloxymethyl group which may optionally be substituted, a carboxyl or an alkoxycarbonyl group, n is an integer of 1 to 20, and provided that n is an integer of 9 to 20 when (0←) is and, at the same time, R2 is a carboxyl group or an alkoxycarbonyl group, or a pharmacologically acceptable salt thereof, have a selective inhibitory action on biosynthesis of thromboxane A, (TXA2) and an effect of enhancing the production of prostaglandin I2(PGI2), and can be used for mammals to prevent and treat arterial thrombosis caused by platelet aggregation or ischemic diseases caused by vaso- spasms in cardiac, cerebral and peripheral circulatory systems (e.g. cardiac infarction, stroke, occlusion of blood vessels in kidney, lung and other organs, peptic ulcer.
    公开号:SU1391500A3
    申请号:SU843772252
    申请日:1984-07-26
    公开日:1988-04-23
    发明作者:Терао Синдзи；Нисикава Кохеи
    申请人:Такеда Кемикал Индастриз,Лтд (Фирма)；
    IPC主号:
    专利说明:

    oo with
    ate

    cm
    This invention relates to a process for the preparation of proeuricular pyridine - new biologically active compounds that can be used in medicine.
    The purpose of the invention is the synthesis of new pyridine derivatives - of low toxicity, which exhibit a stronger and more prolonged inhibitory effect on thrombok san Aj (TXAi) synthetase.
    Example. (E) -7-Phenyl-7- (3-pyridyl) -6-heptenoic acid (1.5 g 5.3 mmol) is dissolved in chloroform (50 ml) and methachloroperbenzoic acid (1, 3 g, purity 70%, 5.3 mmol) with stirring. After 2 hours, the reaction mixture was concentrated under reduced pressure, 30 ml of ethyl acetate was added to the residue, due to which it was obtained in the form of t-7-fesh-7- (1-oxide-3-pyridyl) -6-heptene crystals acid (1.5 g).
    Example 2. (E) -7-phenyl-7- (3-pyridyl) -6-hepten-1-ol (4 g, 15 mmol) is dissolved in chloroform and methachloroperbenzoic acid (3.7%) is added to the solution. g, purity 70%, 15 mmol) with ice cooling. The resulting mixture is heated to room temperature and stirred for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The residue was chromatographed on a silica gel column, eluting with ethyl acetate, and then with ethanol-ethyl acetate, to obtain E-7-phenyl-7- (1-oxyl-3-pyridyl) -5-heptane 1-one (3.3 g).
    In a similar way, as in examples 1 and 2, I get compounds, the physical properties of which are listed in Table. one.
    Biological tests of pyridine derivatives have been carried out.
    Inhibitory effect on synthetase.
    Horseradish microsomes of indomethacin (equine platelet microsomes treated with metacin: IPM) were used as TXA synthetase (IPM), which were obtained according to the procedure described by Nidlemann.
    To 60 µl of 50 mM Tris buffer solution (pH 7.5) of 1PM (containing 140 µg of protein) was added 60 µl of buffer
    a solution or solution containing the test compounds in various concentrations. The mixture is left to stand.
    5 min at room temperature. Then at 0 ° C, 20 µl of a buffer solution containing 30 ng of prostaglandin H2 (PGH2) is added to the yo µl mixture. The mixture is left to stand.
    5 min at 0 ° C, which causes the formation of TXAj. The reaction for the formation of TXA J is stopped by adding 500 µl of Tris buffer to the mixture,
    Using 50 μl mixture with
    Using radioimmunoassay, thromboxin B7 (THB2), which is a stable metabolite of TXAj, is quantitated.
    The inhibitory effect of the compounds on TXA-synthetase is determined by the difference in TCh production in the test and control groups.
    The results obtained using typical compounds are presented in Table 2,
    Test acute toxicity on lpps.
    Male ICP breed mice, age
    5 weeks were used in the experiments in groups of five animals. Each animal was orally administered to each compound to be tested in an amount of 1,000 mg / kg.
    live weight. Next, for 1 week, the dead animals were counted. The results are presented in table 2.
    The tests performed showed
    that the pyridine derivatives obtained by the proposed method belong to the category of mapotoxic and exhibit a higher activity with respect to the inhibition of thromboxane A syntheta45
    Shl.
    Invention Formula
    The method of producing pyridine derivatives of the general formula
    (
    RI where R, is phenyl, thienyl;
    R is methyl, hydroxymethyl, phenyl aminocarbonyloxymethyl, carboxy; methoxycarbonyl; n 4,., 9,
    characterized in that the compound of the general formula
    Q
    (
    RV
    The compounds, of which the pyridyl group is connected to the carbon lithium on the one hand of the olefinic bond, the hydrogen atom is connected to the carbon atom on the other side of the olefinic bond and both are in the same nlpraene, called E-nzo-, and the compounds in which the pyridolic group and a hydrogen atom. Opposite directions, 2-isomers,
    where p, R and R, above, are subjected to oxidation.
    Priority by featured;
    07.27.83 with RI - phenyl, thieyl; R, is hydroxymethyl; n a ... 9.
    04.11о83 with R - phenyl, thienyl; R, is carboxy; п А, „.9.
    T b c in I
    (CH2) nR;
    OKU-046
    Main
    2 -
    OKU 1580
    O-d / s-soon
     / (
    sn.
    Table 2
    -sn-soon
    29
    40
    权利要求:
    Claims (3)
    [1]
    Claim
    The method of obtaining pyridine derivatives of the general formula V - <C = CH- (CH 2 ') n R 2 ' * where R, is phenyl, thienyl;
    R 2 is methyl, hydroxymethyl, phenylaminocarbonyloxymethyl, the carboxy group is methoxycarbonyl;
    n = 4 ... 9.
    characterized in that the compound of the general formula where n, R, and R listed above, subjected to oxidation.
    Priority by signs:
    27.07.83 at R, - phenyl, thienyl;
    R is hydroxymethyl; n = 4. ,, 9, 04.11.83 when R d is phenyl, thienyl;
    R is a carboxy group; n = 4 ,,. 9,
    Connected t.Kaomer- .. - Formula, i.e. ηπ., Β 1 g -oooo 4 € „H„ MO, I 166-167
    Spectrum of Nuclear Research, Z (internal, standard. TMS) 'C
    8.28 (IH); 8, I7 (IH) j 7.26 (7 "), 6.22 (ΪΗ),
    [2]
    2.28 (2H) | 2.16 (2H); 1.58 (4H) with „n„ but 3
    141-142
    8.29 (1H) | 8.2! (1H) | 7.60 (1H) S, 7.29 (7H) |
    6.18 (IH); 2.19 (4H) j 1.56 (4H)
    [3]
    3 O g -COOH 9 C 2 5 H j 5 NO j B.34 HE): 8, 14 (IH); 7.24 (7H); 6.22 (IH); E 102-103 2,31 SAN)) 1.27 (1 AN). 4 Π -COOH 4 CH ,, NO S S 8.31 (IH); 8.22 (IH); 7.50 (1H); 7.25 (ZN); sE 147-148 7.05 (1n); 6.88 (IH); 6, 15 (111); 2,30 (4H) 1,62 (4H) 5 G -COOMe 4 C „H ,, NO, 8.08 (2H); 7.28 (7n): 6.16 (BY) 3.64 (ZN); E Oil 2.17 SAN); 1, 88 SAN) 6 G CH 7-OH 4 Ο ,, Η ,, ΝΟ, 8.09 (2H) j 7.28 (7H); 6.17 (IH); 3.57 (2H); t E Oil 2.16 (2H); 1.41 (6H) 7 G 0CHj-OCNH ^ 4 C J5 H 8.12 (2H), 7.35 (1210; 6.15 (111); ; 4.11 (2H);E Oil 2.08 (2H); 1, 43 (6H)
    • a CH 3 4 C tt Hi, NO 8.08 (2H); 7.28 <7H); 6.17 (1H); 2.11 (2H);
    E Oil 1.28 (6H); 0.81 (EN)
    Note f) Compounds in which a pyridyl group is attached to a carbon atom on one side of an olefinic bond, a hydrogen atom is connected to a carbon atom on the other side of an olefinic bond, and both are in the same direction, are called the E-isomer of NII, and compounds in which a pyridyl group and hydrogen atom. located in opposite directions, - Z-isomers,
    Table 2 on ^ -c = oh (ch 2 VR 2
    Ri
    Testing- R * 2 η Inhibition Sharp my soy waning toxic force Tha -synthetase nost
    OKU-046 Qn-ch 2 - <Q) -ch = sn-soon 29th OKU 1580£> si r <> cn- s-soon sn 340 1 Phenyl soon 4 85 0/5 2- h_ 4 70 0/5 3 9 85 0/5 4 4 90 0/5 5Methoxycarbonyl 4 80 0/5 6 __P_ Hydroxymethyl 4 80 0/5 7 - Phenylaminocarbonyloxy 4 80 0/5 8Methyl 4 68 0/5 9COOH 5 98.6 - 10 6 93.3 - eleven 7 80.0 -
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    同族专利:
    公开号 | 公开日
    KR910003363B1|1991-05-28|
    EP0135316B1|1988-07-13|
    US4563446A|1986-01-07|
    HU194174B|1988-01-28|
    AT35678T|1988-07-15|
    KR850001170A|1985-03-16|
    DE3472674D1|1988-08-18|
    EP0135316A1|1985-03-27|
    CA1257275A|1989-07-11|
    HUT36804A|1985-10-28|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2712020A|1948-07-20|1955-06-28|Burroughs Wellcome Co|Heterocyclic allylamines|
    US3128281A|1961-08-14|1964-04-07|Parke Davis & Co|Amine oxides|
    CA1134828A|1978-12-28|1982-11-02|Tadao Tanouchi|Pyridine derivatives|
    DE3373467D1|1982-06-14|1987-10-15|Takeda Chemical Industries Ltd|Vinyl carboxylic acid derivatives, their production and use|
    US4518602A|1982-10-07|1985-05-21|Takeda Chemical Industries, Ltd.|Vinyl carboxylic acid derivatives, their production and use as inhibitors of thromboxane synthetase|DE3373467D1|1982-06-14|1987-10-15|Takeda Chemical Industries Ltd|Vinyl carboxylic acid derivatives, their production and use|
    US4518602A|1982-10-07|1985-05-21|Takeda Chemical Industries, Ltd.|Vinyl carboxylic acid derivatives, their production and use as inhibitors of thromboxane synthetase|
    AT388728B|1987-03-17|1989-08-25|Hoffmann La Roche|NEW TETRAHYDRONAPHTHALINE AND INDANDERIVATIVES|
    HU205075B|1988-04-04|1992-03-30|Takeda Chemical Industries Ltd|Process for producing substituted vinyl pyridines|
    DE3932403A1|1989-05-12|1991-04-11|Thomae Gmbh Dr K|NEW ARYLSULFONAMIDES, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF|
    KR930700445A|1990-06-07|1993-03-15|원본미기재|Benzoic acid derivatives for the treatment of leukotrienes-related diseases|
    US5849766A|1996-05-31|1998-12-15|Eli Lilly And Company|Carbamoyl substituted heterocycles|
    CA2206466A1|1996-05-31|1997-11-30|Joseph Anthony Jakubowski|Carbamoyl substituted heterocycles|
    JP3839932B2|1996-09-26|2006-11-01|キヤノン株式会社|Process cartridge, electrophotographic image forming apparatus, electrophotographic photosensitive drum and coupling|
    GB9801398D0|1998-01-22|1998-03-18|Anggard Erik E|Chemical compounds|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP13858583A|JPS6028963A|1983-07-27|1983-07-27|Substituted vinyl derivative|
    JP20775983A|JPH0699390B2|1983-11-04|1983-11-04|Substituted vinyl derivative and pharmaceutical composition thereof|
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